Manipulation of the immune system offers a potential modality for the treatment of cancer with high specificity. The primary obstacles have been the difficulty identifying useful target antigens and developing a means of isolating and expanding T cells recognizing these antigens. Tyrosinase has been identified as a potential target antigen for melanoma and our preliminary data demonstrate that it is possible to isolate and expand tyrosinase-specific CD8+ CTL clones from the peripheral blood of patients with melanoma using recombinant vaccinia viruses. However, since these antigens also represent normal self proteins, the use of T cells specific for tyrosinase, in the treatment of metastatic melanoma poses concerns with respect to autoimmune injury. In this study, we investigate the feasibility of isolating antigen-specific tumor-reactive T cells from patients with melanoma and determine, in a clinical trial, the safety, efficacy and in vivo persistence of infused T cell clones.